PO.ET01.06 · 实验与分子治疗
XYD-295和XYD-338：新型亲水性位点特异性连接子平台助力下一代双载荷ADC具备更强的疗效和安全性
XYD-295 and XYD-338: Novel hydrophilic site specific linker platform enables next generation dual payload ADCs with enhanced efficacy and safety
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：抗体偶联药物（ADC）的治疗潜力常受连接子技术的限制。传统疏水性连接子通常导致ADC聚集、血浆快速清除以及在血液和正常组织中的非预期裂解。我们开发了一种新型连接子平台以克服这些挑战，从而能够构建更稳定、更均一、更高效的ADC，包括双载荷形式。
方法：我们的ADC平台设计具备：1）高稳定性以最大程度减少非预期的载荷释放；2）高亲水性以改善溶解性并减少聚集体的形成；3）在肿瘤内高效的酶促裂解和强效载荷的释放。该连接子被位点特异性地偶联到靶向多种抗原（包括DLL3、PD-L1、ADAM9、B7H3、EGFR和cMET）的抗体上，并配备强效载荷，如微管抑制剂和拓扑异构酶I抑制剂，单独或以双载荷形式配备。
结果：使用该新型连接子生成的ADC，与采用传统连接子的ADC相比，在血浆中表现出优越的稳定性和显著更慢的清除率。这些改善的药代动力学特征转化为多种动物模型中更强的抗肿瘤疗效。配备TOP1抑制剂载荷的XYD-295、配备微管抑制剂载荷的XYD-338以及双载荷形式，均在体外和体内表现出增强且协同的肿瘤杀伤。此外，这一设计的连接子支持更高的载药量并减少聚集，在临床前研究中改善了安全性特征，提示更高的治疗指数。基于XYD-295、XYD-338及双载荷形式的多个ADC预计将于2026年进入临床研究。
结论：XYD-295和XYD-338有助于构建更稳定、更均一、更高效的ADC，包括双载荷形式。
查看英文原文 English abstract
Background: The therapeutic potential of Antibody-Drug Conjugates (ADCs) is often limited by linker technology. Conventional hydrophobic linkers usually lead to ADC aggregation, rapid plasma clearance, and undesired cleavage in blood and normal tissues. We have developed a novel linker platform to overcome these challenges, enabling the construction of more stable, homogenous, and efficacious ADCs, including dual-payload formats.
Methods: Our ADC platform was designed to have: 1) High stability to minimize undesired payload release; 2) High hydrophilicity to improve solubility, and reduce the formation of aggregates; and 3) Efficient enzymatic cleavage and release of potent payload within the tumor. This linker was site-specifically conjugated to antibodies targeting diverse antigens (including DLL3, PD-L1, ADAM9, B7H3, EGFR, and cMET) and equipped with potent payloads such as microtubule inhibitor and a topoisomerase I inhibitor, individually or in dual-payload formats.
Results: ADCs generated with this novel linker demonstrated superior stability in plasma and significantly slower clearance rates compared with ADCs with conventional linkers. These improved pharmacokinetic profiles were translated into stronger anti-tumor efficacy in multiple animal models. XYD-295 with TOP1 inhibitor payload, XYD-338 with microtubule inhibitor payload and the dual-payload format, all showed enhanced and synergistic tumor killing in vitro and in vivo. Furthermore, this designed linker supported a higher drug load with reduced aggregation, and improved safety profile in preclinical studies, suggesting a higher therapeutic index. Several ADCs based on XYD-295, XYD-338 and the dual-payload format were expected entry into clinical study in 2026.
Conclusion: XYD-295 and XYD-338 facilitates the construction of more stable, homogenous, and efficacious ADCs, including dual-payload formats
利益披露 Disclosure
W. Ho, None..
P. Rong, None..
M. Zhao, None..
J. Li, None..
X. Zhang, None..
H. Ding, None..
F. Ouyang, None..
J. Wang, None..
J. Xu, None..
Y. Liu, None..
J. Liu, None..
K. Lee, None.